Message to men: One of the strongest risk factors for developing prostate cancer is your family history. This means that if your brother or father had prostate cancer, then your risk for developing the disease is two and a half-fold higher than for a man without family history of the disease. And if you have two affected relatives, your risk is three and a half times higher. Scientists also know from studies carried out in twins (where it is sometimes easier to rule out environmental causes, and focus on genetic factors), that prostate cancer is more heritable than either colon cancer or breast cancer. Genetically speaking, it’s the gift that keeps on giving.

“These are powerful facts,” says molecular geneticist William B. Isaacs, Ph.D., one of the world’s foremost authorities on hereditary prostate cancer, “and they have given us great hope that we can identify one or more genes to explain why prostate cancer runs in families.” Isaacs, the William Thomas Gerrard, Mario Anthony Duhon and Jennifer and John Chalsty Professor of Urology, is a pioneer in this field. In 1996, he and colleagues from Hopkins, the National Human Genome Research Institute, and Umeä University in Sweden reported that there appeared to be a gene or genes located on the long arm of chromosome 1 that increased susceptibility to prostate cancer. Since that time, at least 8 other sites on different chromosomes have similarly been identified.

But the goal of pinpointing these locations exactly hovers tantalizingly out of reach —due, Isaacs believes, to “the very nature of prostate cancer itself.” Because it tends to strike older men, he continues, many different mutations are probably needed to convert a normal cell to a cancer cell —which suggests that there may be many genes involved. “Some of these genes are important in the initiation of the disease,”he continues, “while some are more important in determining which prostate cancers will progress. Also, because the disease occurs in older men, it’s difficult to collect genetic material from multiple generations in a single family.” Another difficulty is that PSA testing — while a godsend for detecting the disease early — may muddy the waters: “It’s often difficult to know which men with prostate cancer truly carry a major cancer susceptibility gene, and which men were detected because of intensive screening.”

To circumvent these roadblocks, Isaacs is aiming big — launching the largest study of

hereditary prostate cancer families ever amassed in the world. The study, headed by Isaacs, combines data from 10 research groups (called the International Consortium for Prostate Cancer Genetics), and involves investigators from the United States, Canada, Norway, Australia, Finland, Germany, and Sweden, and 1,233 prostate cancer families. In a recent study based on these patients, published in the American Journal of Human Genetics, they identified the presence of a significant area of linkage (evidence that a cancer gene is present at this site) on chromosome 22. They also identified five other likely sites of linkage, and are focusing on families in whom multiple men have aggressive prostate cancer.

Why so big? Isaacs reasons that by putting together many families, and by breaking these families down into the ones most likelyt o harbor a mutated gene (families with large number of affected men who developed prostate cancer at an early age), “we’ll have our best shot at determining where these elusive genes are most likely located.”